There are established differences and similarities in phenomenology and treatment between schizophrenia (SCHZ) and major depressive disorder (MDD). It is well known that depressed symptoms occur in SCHZ and psychotic symptoms are no uncommon for MDD. It is therefore justified to postulate that different brain regions and/or different cell types using specith neurotransmitters are crucial to distinguish the neuropathology of both disorders. Neuroimaging evidence implicates the dorsolateral prefrontal (dIPFC) and orbitofrontal (ORB) cortical areas in the neuropathology of SCHZ and MDD. Our recent quantitative histopathological studies in postmortem tissue reveal the differential involvement of the dIPFC and ORB region in the neurobiology of MDD and SCHZ. However, the specific types of neurons and glia, which underlie the prefrontal pathology of these mental disorders have not been identified yet. The overall objective of this proposal is to distinguish MDD and SCFIZ by using quantitative immunohistochemistry to identify the region-and layer-specific biochemical types o vulnerableneurons and glia constituting dysfunctional prefrontal Circuits. The specific hypotheses are: 1) Subjects with MDD will be characterized by lower numbers of immunoreactive neurons and glia and lower levels of trophic factors, BDNF an GDNF in both dIPFC and ORB. In contrast, subjects with SCHZ will exhibit reductions similar to MDD only in the ORI region, whereas in the dIPFC, SCHZ will be distinguished from MDD by higher neuronal and possibly, glial cell number. 2 Cellular changes observed in prefrontal regions from MDD and SCHZ patients are due to the disease process and therefore they will not be found in analogous regions from rat brains treated chronically with antidepressant or antipsychotic medications If these hypotheses are proven, a provocative interpretation would be that anatomic-functional changes in the dIPFC may b related to cognitive dysfunction. Where as changes in the ORB may be related to depressive symptoms. To test these hypotheses vulnerable cell types will be identified and quantified by the combination of immunohistochemistry and 3-D non-biase stereology. We will identify prefrontal cells with specific antibodies (Nonpyramidal neurons with antibodies to Ca2 binding proteins; Pyramidal neurons with antibodies against neurofilament protein NF-200; Astroglia with an antibody to GFAP; ani-Microglia with antibodies against the bchemokine receptor in subjects with MDD, subjects with SCHZ and in match psychiatrically-normal controls. The proposed study will illuminate disrupted cortical circuits involved in psychotic and depressed symptomatology and possibly cortical Sites of action for antidepressant and antipsychotic medications.